PROJECT SUMMARY The goal of this five-year project is to use advanced imaging and biomarker techniques to improve strategies for diagnosing the Acute Respiratory Distress Syndrome (ARDS). ARDS is a common complication of critical illnesses such as sepsis, and affects over 200,000 patients annually in the United States. ARDS mortality exceeds 30%. As yet, few effective therapies have been found. A major reason for this lack of progress is the difficulty in accurately diagnosing ARDS, leading to difficulty in studying potential treatments. ARDS is characterized by inflammation-induced pulmonary edema that leads to severe respiratory failure. However, other conditions such as heart failure (HF) may also cause respiratory failure and pulmonary edema despite having very different pathophysiologic causes, and therefore different treatments. Traditional diagnostic methods include clinical criteria and radiography, which have proven to lack precision in distinguishing ARDS from other illnesses. Recent advances in imaging have demonstrated that lung inflammation and lung edema can be quantified with Computed Tomography/Positron Emission Tomography (PET/CT) scanning, by measuring uptake of 18F-fluorodeoxyglucose uptake (18F-FDG) and 15O-water activity (H215O). A combination of these methods might have potential for improving the diagnosis of ARDS, but has not yet been studied in humans. This project will adapt PET/CT methods to provide functional in vivo lung imaging, with the goal of distinguishing between patients with pulmonary edema due to ARDS and those with pulmonary edema due to HF. This would enable treatment targeted to the underlying biology of the patient's illness, and would help ensure that patients of the appropriate phenotype are enrolled into ARDS clinical studies. This project will also utilize these results to develop a plasma biomarker test for this diagnostic purpose. Specifically, levels of soluble ST2 (sST2), a cytokine receptor that has been studied as novel biomarker of immune tolerance, and which plays a role in myocardial fibrosis and remodeling, will be validated for detection of pulmonary inflammation as demonstrated by PET/CT imaging. Specific aims of the project are as follows: SPECIFIC AIM 1: We will perform PET/CT imaging of critically ill patients to compare lung inflammation (18F- FDG) and pulmonary edema (H215O) in ARDS vs. HF, and compare these with a novel model using 18F-FDG data alone to quantify inflammation and edema. We hypothesize that PET/CT imaging will enable separation of subjects into diagnostic groups according to underlying pulmonary inflammation and edema. SPECIFIC AIM 2: We will test the relationship between lung inflammation and novel biomarker sST2. We hypothesize that plasma concentration of sST2 can be used as a surrogate for imaging to detect lung inflammation, and thus can enable diagnostic separation of subjects according to the presence of this process.